This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with a series of new 2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolinylether derivatives which are phosphodiesterase inhibitors, blood platelet antiaggregators and cardiotonic agents. According to conventional nomenclature, the basic heterocyclic structure can be referred to as 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
As a structural class, relatively few 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones are known to applicants with the following chemical literature illustrative of the art.
Kozak, et al., Bull. Intern. Acad. Polanaise, 1930A, 432-438 (Chem. Abs. 25, 5400) describes the unsubstituted compound 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one of formula (1). ##STR2##
Musial, Roczniki Chem., 1951, 25, 46-52 (Chem. Abs., 1953, 47, 4885f) synthesized 1,3-derivatives of (1) as illustrated in formula (2). ##STR3##
Fryer, et al., J. Org. Chem., 1977, 42, 2212-2219 describes the 3,7,9-trisubstituted compound of formula (3). ##STR4##
Reid, et al., Chem. Ber., 1956, 89, 2684-2687 describes the synthesis of the 1,3-diphenyl derivative of formula (4). ##STR5##
No pharmacological utility is taught for the 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one structures disclosed in the aforementioned references which are of a chemical nature.
Various derivatives of the tetrahydroimidazo[2,1-b]quinazolin-2-one (5) heterocycle have been studied for their platelet inhibition and cardiotonic properties. ##STR6## For example:
Beverung, Jr., et al., U.S. Pat. No. 3,932,407 disclose a series of compounds useful as blood platelet antiaggregative and/or antihypertensive and/or bronchodilator agents of the tetrahydroimidazo[2,1-b]quinazolin-2-one class. Anagrelide (6), a particularly preferred member of the Beverung, Jr., et al. series, has been studied extensively, e.g., J. S. Fleming, et al., New Drugs Annual: Cardiovascular Drugs, Raven Press, pages 277-294, New York (1983). ##STR7##
Chodnekar, et al., U.S. Pat. No. 4,256,748 describes a series of tetrahydroimidazo[2,1-b]quinazolin-2-ones of the formula (7) as inhibitors of the aggregation of blood platelets and cardiotonic activity. ##STR8## Representative of the Chodneker compounds are RO 15-2041 (R.sup.4 .dbd.CH.sub.3, R.sup.3 .dbd.H, R.sup.2 .dbd.6--CH.sub.3, R.sup.1 .dbd.7--Br) and RO 13-6438 (R.sup.4 .dbd.CH.sub.3, R.sup.3 .dbd.H, R.sup.2 .dbd.6--CH.sub.3, R.sup.1 .dbd.H).
Jones, et al., U.S. Pat. No. 4,490,371 describes another series of tetrahydroimidazo[2,1-b]quinazolin-2-one derivatives as cyclic AMP phosphodiesterase inhibitors useful as thrombogenic agents. Among the compounds disclosed is the formula (8) amide, identified in the art as RS82856. ##STR9##
Jones, et al., European Patent Application No. 153152 further describes tetrahydroimidazo[2,1-b]quinazolin-2-ones of formula (9) as cyclic AMP phosphodiesterase inhibitors useful as antithrombogenic agents. ##STR10##